美国斯坦福大学Humsa S. Venkatesh课题组报道了小细胞肺癌发病的神经元活动依赖机制。2025年9月10日出版的《自然》杂志发表了这项成果。

本研究表明，在肺中，迷走神经横断明显抑制原发性肺肿瘤的发展和进展，突出了神经支配在SCLC生长中的关键作用。在大脑中，SCLC细胞通过神经元活动调节机制来刺激生长和进展。谷氨酸能和伽马氨基丁酸（γ-氨基丁酸产生）皮质神经元的活性分别通过旁分泌和突触神经元与肿瘤的相互作用驱动大脑中SCLC的增殖。SCLC细胞形成真正的神经元到SCLC突触，并表现出去极化电流，随之而来的钙瞬态响应神经元活动；这种SCLC细胞膜去极化足以促进颅内肿瘤的生长。总之，这些发现阐明了神经元活动在SCLC发病机制中起着至关重要的作用。

据悉，神经活动越来越被认为是癌症生长的关键调节器。在大脑中，神经元活动通过旁分泌机制和恶性细胞通过神经元到胶质瘤突触的电化学整合进入神经回路，从而对胶质瘤的生长产生明显影响。在中枢神经系统之外，前列腺癌、头颈癌、乳腺癌、胰腺癌和胃肠道癌等肿瘤通过周围神经的神经支配同样调节癌症的进展。然而，神经系统在多大程度上调节小细胞肺癌（SCLC）的进展，无论是在肺部还是在大脑内生长，都不太清楚。SCLC是一种致死性高级别神经内分泌肿瘤，表现出强烈的脑转移倾向。

附：英文原文

Title: Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis

Author: Savchuk, Solomiia, Gentry, Kaylee M., Wang, Wengang, Carleton, Elana, Biagi-Junior, Carlos A. O., Luthria, Karan, Yaln, Belgin, Ni, Lijun, Farnsworth, Hannah C., Davis, Rachel A., Drexler, Richard, Melms, Johannes C., Liu, Yin, Acosta-Alvarez, Lehi, Hartmann, Griffin G., Pavarino, Elisa C., LaBelle, Jenna, Woo, Pamelyn J., Toland, Angus M., Qu, Fangfei, Kim, Yoon Seok, Filbin, Mariella G., Krasnow, Mark A., Ligon, Keith L., Izar, Benjamin, Sage, Julien, Sabatini, Bernardo L., Monje, Michelle, Venkatesh, Humsa S.

Issue&Volume: 2025-09-10

Abstract: Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth through paracrine mechanisms1 and by electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses2,3. Outside of the central nervous system, innervation of tumours such as prostate, head and neck, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression4,5,6,7,8,9,10,11,12. However, the extent to which the nervous system regulates small cell lung cancer (SCLC) progression, either in the lung or when growing within the brain, is less well understood. SCLC is a lethal high-grade neuroendocrine tumour that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that in the lung, vagus nerve transection markedly inhibits primary lung tumour development and progression, highlighting a critical role for innervation in SCLC growth. In the brain, SCLC cells co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity each drive proliferation of SCLC in the brain through paracrine and synaptic neuron–cancer interactions. SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity; such SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumours. Together, these findings illustrate that neuronal activity has a crucial role in dictating SCLC pathogenesis.

DOI: 10.1038/s41586-025-09492-z

Source: https://www.nature.com/articles/s41586-025-09492-z